New ground broken in epilepsy research

2 new culprits, many mutations linked to disease

The largest genetic study of children with certain debilitating types of epilepsy has uncovered dozens of mutations associated with the disease and two genes that have never before been linked to epilepsy, opening new avenues of research into potential treatments.

The results - published Sunday in the journal Nature - are the first from an extensive nationwide project, led by researchers at UCSF and Duke University, to analyze the genomes of children with epilepsy. The findings focused on children with the most severe forms of epilepsy, which often are untreatable and cause major cognitive and developmental disabilities.

The study won't have an immediate effect on how those epilepsies are treated or diagnosed. But it could lead to new targets for drug therapy and better understanding of all types of epilepsy, which is still in many ways a neurological mystery.

"This broadens our view of the different kinds of neurological pathways that can be altered and lead to epilepsy," said Dr. Elliott Sherr, a UCSF neurologist who led the study. "This research may point us to different drug therapies. Maybe we could start to screen for these epilepsies before kids get them. Could we potentially treat them with medicine at birth and reduce or even prevent epilepsy?"

Precision medicine

The epilepsy genome project is part of a growing field of research in precision, or personalized, medicine. The idea is to target treatment of a disease to its genetic makeup - hunting for drugs that attack a specific biological target, or that are known to cause fewer side effects in people with certain genetic mutations.

Epilepsy is a condition marked by chronic seizures. It's thought to affect about 10 percent of children, although most kids outgrow their seizures and suffer few, if any, long-term effects into adulthood. Some forms of epilepsy can be caused by an injury - such as a pre-birth stroke or a head trauma in infancy - and others are inherited. But in a large number of cases, a cause is never found.

There are dozens of drugs available that can help prevent seizures or make them less severe, but those medicines don't treat the underlying cause of epilepsy - whatever biologically is happening in the brain - and they don't work for a lot of children.

"When I see parents, they have three questions: Why did my child get epilepsy, which medication is best, and will it cause side effects?" said Dr. Dan Lowenstein, a UCSF neuroscientist who helps oversee the epilepsy genome project. "And I can't answer any of those questions. The work we're doing - that's why we're doing it. We have to move beyond the current state of care for patients with epilepsy."

Birth of an idea

The concept of the epilepsy project came from a group of pediatric neurologists more than 10 years ago, just as the human genome was sequenced for the first time and scientists were anticipating the potential for future research into all kinds of diseases.

In 2007, those neurologists, all epilepsy specialists, started the Epilepsy Phenome/Genome Project with funding from the National Institutes of Health. That project involved collecting DNA samples and health data on more than 4,000 epilepsy patients and their parents around the country. In 2012, the group launched a second phase of the project, called Epi4K, to begin sequencing the genomes of those patients and parents.

The study published Sunday looked at the first results from the genome sequencing, focusing on patients with severe forms of the disorder known, collectively, as epileptic encephalopathies. These seizure disorders are rare, affecting about 1 in 2,000 children in the United States, but they can be extremely disabling.

There often is no known cause for epileptic encephalopathies, and unlike some other epilepsies, they usually aren't inherited from a parent. That has led many doctors to theorize that these types of epilepsy are caused by sudden mutations in certain genes that probably happen very early in fetal development - maybe even in the egg or sperm of the parent.

Comparing genomes

In the study, researchers looked for those sudden mutations by comparing the genomes of 264 children, all with epileptic encephalopathies with no obvious cause, to the genomes of their parents.

Bolstering their theory, the scientists identified dozens of mutations and pinpointed nine genes where these mutations were located. Seven of those genes already had been identified as likely culprits in epilepsy, but two were new discoveries.

Of special interest is that one of the new genes also has been implicated in a neurological disorder called Angelman syndrome, for which there is a drug that is very effective. Scientists hope that the same drug may be useful in treating epileptic encephalopathies.

Scientists also hope that identifying new genes, and new genetic mutations, will improve their understanding of how epilepsy affects the brain, and where certain biological processes go wrong.

Using the new genetic information, scientists may take drugs already developed and test them in a lab setting to see if they have any effect on the epilepsy gene mutations. If they can find drugs that block the effects of a certain mutation, they may be able to slow down or even stop the disease.

"Our treatment hasn't really progressed tremendously in decades," said Dr. Rachel Kuperman, medical director of the epilepsy program at Oakland Children's Hospital, who helped recruit patients for the national study. "We're nowhere near where we are with, say, cancer, where we can look at the genome and know this drug will work. Instead we're throwing drugs at patients, hoping they'll work better than the last drug.

"Hopefully, the basic scientists will get to work now and get us some treatments and answers," she said.

Study participant

Stockton resident Neva Hirschkorn, whose son Sean participated in the UCSF study, said the information collected from this research will almost definitely come too late to help her child. Sean, 24, has a severe form of epilepsy that has left him needing around-the-clock care since he was about 10.

Hirschkorn said genetic testing should be done for almost all children with epilepsy, because scientists already have discovered that certain drugs work better on certain types of the disease. In her son's case, she believes he was given drugs for many years that actually were harmful for someone with his type of epilepsy, called Dravet syndrome.

But genetic testing wasn't available when he was a child. In fact, she only got the tests for him last month, and he's since been switched to different medications.

"Now that I have this information for my son, I want to pay it forward," Hirschkorn said. "We've got to get parents aware of precision medication, aware of genetic testing. If you can get the kids on the right medication and treatment, they may have a fighting chance."